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Ketamine for Chronic Pain? What the Latest Cochrane Review Really Says
- Asian Pain Academy
- 2 days ago
- 5 min read
Updated: 1 day ago
Introduction
The idea of using ketamine for chronic pain has fascinated pain specialists for decades. Known initially as a dissociative anesthetic, ketamine found renewed interest as an analgesic, particularly in refractory pain conditions where conventional options fail. With its unique action on N-methyl-D-aspartate (NMDA) receptors, ketamine has been thought to modulate central sensitization—a key mechanism in persistent pain.
Alongside ketamine, other NMDA receptor antagonists such as memantine, dextromethorphan, amantadine, and magnesium have been studied for their potential role in pain relief. However, the real-world evidence for these therapies has been uncertain and often contradictory.
In August 2025, a landmark Cochrane Review was published, synthesizing data from 67 randomized controlled trials. This review represents the most rigorous attempt yet to answer the pressing question: Does ketamine for chronic pain truly work?
Why NMDA Antagonists Were Considered for Pain
Chronic pain often involves central sensitization, where the nervous system becomes hypersensitive, amplifying pain signals. The NMDA receptor plays a central role in this process.
Ketamine, by blocking NMDA receptors, was believed to “reset” hypersensitized pain pathways.
Memantine and amantadine, better known for their use in neurological conditions, were thought to provide milder NMDA blockade with fewer psychotropic side effects.
Dextromethorphan, a cough suppressant, also acts on NMDA receptors and has been trialed in neuropathic pain.
Magnesium, a physiological NMDA antagonist, has long been studied for its adjuvant role in perioperative and chronic pain control.
Despite these theoretical advantages, the clinical evidence has always been patchy, prompting the need for a large systematic review.
Scope of the Cochrane Review on Ketamine for Chronic Pain
Number of studies: 67 randomized controlled trials
Participants: 2,309 adults with chronic, non-cancer, non-headache pain lasting more than 3 months
Medications evaluated: Ketamine, memantine, dextromethorphan, amantadine, magnesium
Comparisons: Placebo, standard care, or other analgesics
Search methods: Comprehensive search of CENTRAL, MEDLINE, Embase, and clinical trial registries up to June 2025
This makes it one of the most robust systematic analyses on the subject, focusing exclusively on chronic pain rather than perioperative or acute settings.
Findings: Ketamine for Chronic Pain
1. Efficacy of Ketamine and Other NMDA Antagonists
Across intravenous, oral, and topical routes, ketamine showed no consistent evidence of meaningful pain reduction.
Other NMDA antagonists—memantine, dextromethorphan, amantadine, magnesium—also did not provide clinically significant or reproducible pain relief.
Benefits, when seen, were typically short-lived and inconsistent across trials.
2. Adverse Effects and Risks
Particularly concerning was intravenous ketamine for chronic pain, which carried a higher risk of adverse effects, including:
Psychotomimetic effects: hallucinations, dissociation, altered perception
Nausea and vomiting
Rare but reported cardiovascular side effects (tachycardia, hypertension)
For other NMDA antagonists, the data were too limited to establish clear safety profiles.
3. Quality and Certainty of Evidence
The review rated the certainty of evidence as low to very low, largely because of:
Small sample sizes (many trials had <50 participants)
Short follow-up periods (often days to weeks, not months to years)
Variability in dosing, routes, and patient populations
This means current evidence cannot be considered strong enough to make reliable clinical recommendations.
Authors’ Conclusion: Ketamine for Chronic Pain
The review concludes that current evidence does not support ketamine or other NMDA receptor antagonists as reliable, effective treatments for chronic non-cancer pain.
While ketamine has been promoted as an option for refractory cases, the findings emphasize that potential harms may outweigh uncertain benefits, especially with intravenous use.
The authors strongly advocate for larger, high-quality clinical trials with longer follow-ups to properly assess efficacy and safety.
Why Clinicians Still Use Ketamine for Chronic Pain
Despite the weak evidence base, ketamine continues to be used in some pain clinics worldwide. Reasons include:
Desperation in refractory cases, where patients have exhausted conventional treatments.
Anecdotal short-term benefits in neuropathic pain and CRPS (Complex Regional Pain Syndrome).
It has dual use in depression and pain, where an overlap exists in patient populations.
However, this Cochrane Review reminds clinicians that such practices are based more on hope and anecdote than on solid evidence.
Clinical Implications
For pain specialists, the practical takeaways are clear:
Off-label use of ketamine for chronic pain should be restricted and carefully monitored.
Patients should be given balanced counseling, considering both the potential short-term benefits and the risk of side effects.
Clinicians must integrate multimodal pain management: physical therapy, cognitive-behavioral therapy, interventional blocks, and evidence-based pharmacology.
Future practice should shift toward participating in clinical trials rather than widespread empirical use.
Why This Matters for Pain Medicine Education
At the Asian Pain Academy, we emphasize critical appraisal of evidence before integrating new therapies into clinical practice.
This review illustrates three important lessons for doctors in training:
Not all mechanistic theories translate into effective clinical treatments.
Safety must remain a priority, especially when evidence for efficacy is weak.
Global collaboration is needed to generate strong clinical trial data in pain medicine.
By keeping our fellows and participants updated with such evidence, we ensure that they practice pain medicine with both innovation and caution.
FAQ: Ketamine for Chronic Pain
Ketamine & Chronic Pain – Quick Reference (Based on Cochrane Review 2025)
❓ Question | 📌 Evidence / Answer | ⚠️ Notes |
1. Does ketamine work for chronic pain? | ❌ No – no clear or consistent evidence of reducing chronic pain intensity. | 🔎 Not reliable as routine therapy. |
2. What are the side effects of ketamine infusions? | ⚠️ Hallucinations, dissociation, nausea, vomiting, cardiovascular changes (↑/↓ blood pressure & heart rate). | 👀 Requires close monitoring. |
3. What did the Cochrane Review 2025 conclude? | 📉 Evidence is weak and uncertain — ketamine cannot be recommended as reliable chronic pain treatment. | ✅ Only consider with caution. |
4. Are other NMDA antagonists effective? | 🚫 Memantine, amantadine, dextromethorphan, magnesium → no consistent benefit. | 🔄 Limited clinical role. |
5. Should ketamine still be used in pain clinics? | 🟡 Only in rare, refractory cases, with strict monitoring, preferably within a research or trial setting. | 🧪 Use as experimental/last-resort option. |
✨ This way:
❌ / 🚫 = Negative evidence
⚠️ = Safety concerns
📉 = Weak evidence
🟡 = Conditional/rare use
References
Cochrane Pain, Palliative and Supportive Care Group. Ketamine and other NMDA receptor antagonists for chronic pain. Cochrane Database of Systematic Reviews 2025, Issue 8. Art. No.: CD015373. DOI: 10.1002/14651858.CD015373.pub2
EurekAlert. Lack of evidence supports ketamine use in chronic pain management. August 2025.
PubMed. Cochrane Review abstract: Ketamine and NMDA receptor antagonists for chronic pain.
Final Thoughts
The latest Cochrane Review reinforces an uncomfortable truth: while ketamine for chronic pain has generated excitement, the scientific evidence is weak, inconsistent, and limited by risks.
For now, ketamine and other NMDA antagonists should be viewed as experimental options, not standard care. Clinicians must prioritize proven multimodal strategies while awaiting stronger research.
👉 Learn more about evidence-based pain medicine and advanced training at Asian Pain Academy.
